Current treatment protocols for AIDS involve combinations of nucleoside analogs and HIV protease inhibitors, but are not successful in curing the disease. The drug transport protein, P-glycoprotein (Pgp) effluxes a wide variety of drugs, including all FDA-approved protease inhibitors. A growing body of evidence indicates that inhibiting Pgp will enhance AIDS chemotherapy by improving the delivery of protease inhibitors to the brain, improving their oral bioavailability, and enhancing the perinatal exposure of the fetus to these drugs. The closely related transporter MRP1 is expressed by all normal tissues, so that inhibition of this protein increases drug toxicity in non-target tissues. The goal of this project is to develop new compounds that selectively inhibit Pgp to be used in combination with protease inhibitors in the therapy and prevention of AIDS. Compounds PGP- 4008 and PGP-3005 are structurally novel compounds that demonstrate excellent antagonism of Pgp in vitro, without affecting MRP1 activity. We will examine the potential utility of these compounds by determining their effects on 1) Pgp-mediated transport of protease inhibitors in vitro; and 2) the pharmacokinetics and biodistribution of protease inhibitors in vivo. These studies should allow a critical evaluation of the potential utility of these novel compounds in the improvement of AIDS chemotherapy. PROPOSED COMMERCIAL APPLICATION: Combination chemotherapy including protease inhibitors is the current optimal care for the 850,000 Americans and 36,000,000 people worldwide infected with the HIV virus. Chemotherapy regimens average approximately $10,000 per year in the U.S. Successful improvement of chemotherapy with the compounds under study would have enormous economic and humanitarian impact on this disease.